Huda Zoghbi has been a major contributor over the years to our understanding of genes and gene regulation in brain diseases, such as Rett syndrome. Here she and collaborators report on the neurobiological and behavioral impact of increased expression of the gene SHANK3, which has been implicated in autism, schizophrenia, and neurodevelopmental disorders. Patients with 22q13.3 deletion syndrome—involving SHANK3 and a variable number of contiguous genes—are occasionally diagnosed with bipolar disorder in the context of diverse neuropsychiatric symptoms, but little is known about the even rarer 22q13 duplications which presumably increase gene dosage. Here, Han et al. report that transgenic mice engineered to overexpress Shank3 exhibit abnormal behavior and seizures that are responsive to valproate. Han et al. further show that Shank3 directly interacts with the Arp2/3 complex to increase F-actin levels at the synapse.

This paper is a nice example of how animal models and systems biology can be combined to illuminate the extremely complex effects of key proteins in the brain. I do have a problem with the authors' conclusion that the results "suggest that ~50 percent increase in Shank3 level causes a hyperkinetic phenotype in mice that resembles mania." The overexpressing mice did show hyperactivity, decreased immobility on tail suspension, unusual circadian activity, and response to valproate—all of which are typically reported in rodent models of mania and are broadly consistent with manic episodes in humans. However, Shank3 overexpressing mice also displayed decreased social interaction, decreased ultrasonic vocalization, and lack of response to lithium, which are strongly inconsistent with mania. Hedonic behavior and aggression were not reported.

So this paper tells us a lot of valuable new information about the role of Shank3 on neuronal function, but the paper suffers from a too strong reliance on partial behavioral resemblances with mania in humans. As the field moves toward cellular models enabled by induced pluripotent stem cell technology, it may finally be possible to make a clean break from anthropomorphic dependence on behavioral "resemblances" and move toward the molecular components which are truly conserved across organisms. Meanwhile, genetic studies in human patients are still the best way to form strong hypotheses about genes involved in disease and treatment response.

Instead of asking whether a particular animal model is "valid" as a proxy for a particular psychiatric disorder, we should be asking, Is it useful? Can it tell us something we can't learn in humans? If we base that solely on supposed behavioral similarities, we haven't gotten very far—we might as well just be doing rodent psychoanalysis. What we are interested in is elucidating the underlying neurobiological abnormalities and the pathways from etiological factors to resultant pathophysiological states. Such states should be expected to affect behaviors in a species-specific manner—maybe there will be some surface similarity in the results between rodents and humans, but maybe not. Certainly, expecting any animal model to recapitulate the full profile of human symptoms associated with a particular psychiatric diagnostic category is asking too much—does any human patient model the entire spectrum of disease? If these diagnostic categories are really umbrella terms for hundreds of distinct genetic conditions, each with variable outcomes, then the focus in models should be more on the expression of particular symptom domains than on entire disease profiles.

Starting with strong etiological factors is a proven route to discovery of pathogenic mechanisms. As such, the SHANK3 duplication mice are more inherently relevant to disease than the calcineurin mice, which are an artificial transgenic line not directly representative of any human patient. Indeed, the genetic evidence implicating calcineurin in schizophrenia risk has effectively been superseded by negative results from very large GWASs (unless it has popped up again in the unpublished results of the PGC). It is, nevertheless, a very interesting genetic preparation that can be used to dissect circuit mechanisms of memory, which clearly are of relevance to several disease states. That really ought to be enough to garner a wide readership without resorting to claims of direct disease model validity.

There is a classic catch-22 in an attempt to model schizophrenia (and other major mental disorders) as, on the one hand, the main purpose of creating a model is to discover the cause of illness (e.g., a genetic defect and the subsequent pathological processes underlying the disease), and on the other hand, it is unclear what to model because the etiology of schizophrenia is still not well understood. Many new models focus on genetic causes because of the strong evidence for heritability of mental illness and the recent discoveries of particular predisposing genes. It is also becoming clear that in most cases, no single gene is necessary or sufficient to cause the disease, but instead, common, low-penetrance genetic variants in more than one susceptibility gene, each contributing a small effect, act in combinations to increase the risk of illness. In some other cases it is possible that rare, but highly penetrant, mutations (i.e., point mutations, translocations, deletions) in single genes are responsible. It is also increasingly clear that there are interactions among susceptibility genes, and between genes and environmental factors that contribute to the risk for mental illness. Given all this, there is no doubt that the task of modeling schizophrenia in animals is formidably difficult.

It is further complicated by the fact that a gene-based animal model 1) may have to be related to a specifically human transcript and/or protein variant or variants artificially introduced into the animal; 2) will not exhibit abnormalities in all schizophrenia-related phenotypes (as animals will not have hallucinations or delusions); and 3) may require additional environmental manipulations to become fully penetrant at the behavioral level. We should thus perhaps accept the fact that a mouse model for an individual candidate gene will never be representative of the entire disorder, and at best it will reproduce either a subtype of the disorder or a particular aspect of a given phenotype. In that context, human cell-based models and studies of human brain tissues obtained postmortem from patients with mental illness (severely underutilized resources!) are perhaps better alternatives to gain insight into the origins and pathophysiology of these specifically human, challenging disorders.

I think that we are often making a mistake if we directly declare what disease are we modeling. There are no "valid" animal models of human schizophrenia or other major psychiatric disorders, and most likely, there will never be—the mouse is not a human, and has a quite different lifestyle! Furthermore, the mouse and the human genetic diversity are quite distinct. Thus, talking about modeling physiological and pathophysiological processes is much more correct. Understanding behavioral modulation by the various interneuronal subtypes, evaluating the role of gene X on cortical lamination, or assessing the effects of factor Y on neuronal outgrowth are all disease-relevant, essential studies.